A major area in the clinical application of biomaterials that presents a formidable challenge to clinicians, material scientists, and bioengineers pertains to their use for the repair/replacement of bone tissues and particularly craniomaxillofacial bones. Related to this are (1) the inability of most biomaterials to form an active interface with natural tissues; (2) the limited availability of materials with tailored half life to allow the natural tissues to grow gradually and predictably into defective sites, temporarily occupied by a transient absorbable scaffold designed to support bone ingrowth; (3) scarcity of biomaterials that can be applied easily and precisely in irregular defective sites; (4) lack of bioactive biomaterial inserts or scaffolds for bone regeneration that conform to irregular structurally defective sites and transform into solid articles having a modulus that approaches those of typical bones; and (5) complications associated with occasional release of transition metallic ions from metallic implants that may cause allergic reactions in certain patients. Although great efforts were directed towards addressing these issues in orthopedic implants, limited attention was given to craniomaxillofacial implants. The promise of tissue engineering and particularly, directed tissue ingrowth about the implant, or what can be denoted, in situ tissue engineering, have created new, practical directions in dealing with current implants for bone repair or replacement. The latter are mostly metallic and designed for mechanical interlocking with bone or use in conjunction with bone cement.
In spite of the relatively limited attention given to the craniomaxillofacial implants by clinicians pertinent to concerns about the use of metallic materials, impressive efforts have been made by biomaterial scientists to explore the use of absorbable polymeric materials. This is understandable if one acknowledges the fact that in most craniomaxillofacial applications, the load-bearing requirements for the implants are generally much lower than those noted for orthopedic implants. And the less demanding mechanical requirements for craniomaxillofacial implants were very much in concert with the relatively low modulus of polymers as compared to metals. This, in turn, provided a strong incentive to explore the use of bioabsorbable polymers over the last three decades. However, limited availability of these polymers in terms of types and forms has compromised their acceptance by clinicians. Of the craniomaxillofacial family of implants, the maxillofacial subfamily, and more specifically, the intraoral implants, attracted the attention of most investigators. In their study of the intraoral implants, these investigators used absorbable polymers for repairing maxillary, mandibular, and facial bone defects. Commercial and experimental polymers used by these investigators were, for the most part, based on homopolymers such as poly(l-lactide) (PLLA), random copolymers of l-lactide/dl-lactide (PDLL), l-lactide/trimethylene carbonate (PLL/TMC), polyglycolide (PGA), terpolymers of l-lactide, d-lactide and glycolide (PDLLG), self-reinforced polyglycolide (SR-PGA), and to a lesser extent, poly p-dioxanone (PDS), as well as blends of these polymers. Unfortunately, in most of the explored applications, these materials did not meet fully the general requirements for successful craniomaxillofacial and particularly the intraoral, implants, namely: (1) mechanical and chemical stability during the expected period of functional performance; (2) biomechanical compatibility of the implant and surrounding bone, primarily in terms of modulus; (3) ability to support osseointegration and, hence, a timely healing and mechanical stability; and (4) ease of fabrication and shape modulation. Applications of bioabsorbable polymers as maxillofacial surgical implants have been reviewed by Mayer and Hollinger [Chapter 9 in Biomedical Applications of Synthetic Biodegradable Polymer, J. O. Hollinger, Ed., CRC Press, New York, 1995]. Most of these and more recent applications dealt with the use of (1) PLA sutures for internal fixation of iatrogenic mandibular symphysis fracture in monkeys; (2) PDLLA rods for the fixation of mandibular fractures in monkeys; (3) PLA plates and screws for reducing mandibular fractures in monkeys; (4) PDS lag screws for the fixation of a fracture of the mandibular angle; (5) PLA/PGA bone plates reinforced with PGA fabric for repairing mandibular and skull fractures; (6) PDS plates for orbital floor reconstruction; (7) SR-PLLA plates for the fixation of unfavorable transverse osteotomies; and (8) PLA plates and screws for the fixation of zygomatic arch fractures in rabbit. In practically all of the aforementioned craniomaxillofacial applications, the type of polymeric materials and the form of the implants were less than ideal because the limitation imposed on the clinical and scientific investigators in terms of availability of site-specific polymer types and forms. And this was the driving force to pursue the present invention.
Accordingly, this invention deals with an absorbable microparticulate mixture encased in a textile construct to form a sealed conformable article which transforms to a biocompatible, rigid mass that supports bone regeneration as part of in situ (or locally directed) tissue engineering. Although there have been a large number of citations in the prior art dealing with bone regeneration, none has dealt with the novel approach to bone regeneration described in this invention. Typical examples of the prior art are outlined below.
In an approach to the development of a novel scaffold for bone tissue engineering, Zhang and Zhang [Journal of Biomedical Material Research, 61, 1, (2002)] prepared a three-dimensional composite scaffold of macroporous HAP/β-TCP bioceramic matrices nesting chitosan. In comparison with pure porous bioceramics, the nested chitosan sponges enhanced the mechanical strength via reinforcement of the bioceramic matrix. The nested chitosan sponges also caused the composite scaffolds to have a high surface area/volume ratio leading to an increase in the number of cells adhered to the composite scaffolds. The results of the simulated body fluid experiments showed that a high density of randomly oriented, needlelike apatites have grown on the scaffold surface, suggesting that the material has good bioactivity. The cell culture experiments showed that MG63 osteoblast cells were attached and proliferated on the surface of the composite scaffold and migrated onto the pore walls. The cells have almost the same alkaline phosphatase activity on the composite scaffolds as on tissue culture dishes during the first 11 days of culture.
Towards the development of a new bone substitute material, Yokoyama and coworkers [Biomaterials, 23, 1091, (2002)] prepared a calcium phosphate cement that consists of chitosan, glucose, and citric acid solution as the liquid component, and tricalcium phosphate (α-TCP) and tetracalcium phosphate (TeCP) as the powder components. This cement could be molded to desired shape because of its chewing-gum-like consistency after mixing, and it demonstrated good biocompatibility in both soft and hard tissues. In this study, liquid components of 20% and 45% citric acid were used to investigate the influence of acid, and the results indicated that the concentration of citric acid in the liquid component influences both the mechanical properties and biocompatibility of the cement.
A communication by Zhao and coworkers [Biomaterials, 23, 3227, (2002)] described the preparation and histological evaluation of biomimetic, three-dimensional hydroxyapatite/chitosan-gelatin (HAP/CS-Gel) network as a composite scaffold for bone tissue engineering. In their study, the authors demonstrated the feasibility of using the phase separation technique to prepare such a scaffold. They further showed adhesion, proliferation, and expression of rat calvaria osteoblasts on these highly porous scaffolds. The HAP/CS-Gel composite scaffolds were characterized by their biomimetic composition, and further studies on cell densities, porosities of scaffolds as ell as in vivo implantation are underway.
Consistent findings on the role of zinc in bone growth prompted recent studies on the development and effectiveness of zinc-releasing calcium phosphate ceramics to promote bone formation with zinc-containing β-calcium phosphate (ZnTCP) ceramics as the zinc carrier [Kawamura, H. et al., Journal of Biomedical Material Research, 50, 184 (2000)]. A representative ceramic composite was made of ZnTCP and hydroxyapatite (HAP) having a Ca/P molar ratio of 1.60 at ZnTCP/HAP of 1.60. Thus, this composite was found to significantly promote mouse osteoblastic MC3T3-E1 cell proliferation in vitro at a zinc content of 1.2 weight percent. And bone formation about 1.60 ZnTCP/HAP implant in rabbit femur increased by 51% at zinc content of 0.316 weight percent in comparison with a composite of the same Ca/P molar ratio without zinc. Bone formation around monophasic ZnTCP implants in rabbit femora appeared to be a function of zinc content with a maximum bone formation at 00.316 weight percent. Interestingly, there was no statistically significant difference in the maximum bone formation due to ZnTCP and β-tricalcium phosphate at the same weight percent.
Bone morphogenic proteins (BMPs) have been shown to stimulate the production of bone in vivo when combined with an appropriate carrier material, such as collagen, calcium phosphate, or 2-hydroxyacid polymers [Ursit, M. R. in Encyclopedia Handbook of Biomaterials & Bioengineering—Materials and Applications, Vol. 1, Marcel Dekker, New York, 1995, pp. 1093-1122]. Recognizing the potential need for a puttylike absorbable matrix, which can be molded into shape of the desired new bone and hardened in situ by contact with aqueous fluids led Andriano and coworkers [J. Biomedical Material Research—Applied Biomaterials, 53, 36 (2000)] to develop a liquid polymer system consisting of lactide-glycolide copolymers dissolved in a “biocompatible” solvent which solidifies in situ by contact with aqueous fluid. The pursuit of this study was consistent with an earlier study by Chandrashekar and coworkers [Proceedings of Portland Bone Symposium, Portland, Oreg., August 1997, pp. 583-587] who incorporated BMPs in the same type of polymeric carrier system and used it to promote bone ingrowth in ectopic and orthotopic sites, such as subcutaneous and skull onlay, respectively. In their in vivo study of osteogenic potential BMPs delivered from the puttylike matrix, Andriano and coworkers first incorporated the proteins in a polymer matrix consisting of 50/50 poly(DL-lactide-co-glycolide) dissolved in N-methyl-2-pyrrolidone. The matrix was implanted in an 8 mm critical-size calvarial defect created in the skull of adult Sprague-Dawley rats (n=5 per treatment group). After 28 days, the implant sites were removed and examined for new bone formation, polymer degradation, and tissue reaction. Gamma-irradiated polymer matrices appeared to give more bone formation than non-irradiated samples (histological analysis: 2.76±1.34 mm2 of bone versus 1.30±0.90 mm2 of bone, respectively, and X-ray analysis: 27.2±15.9 mm2 of bone versus 20.7±16.7 mm2 of bone, respectively) and less residual polymer (0.0±0.0 versus 0.2±0.4, respectively). The polymer implants with bone morphogenic proteins also gave less inflammatory response than the polymer controls (gamma irradiated polymer/BMPs=1.8±0.4 and non-irradiated polymer/BMPs=1.2±0.4 versus polymer only=3.0±1.2, respectively).